Mechanisms
A disease-associated CETP mutation drives amyloid formation and cytotoxicity in vitro (Int J Mol Sci 2011)
Original title: Amyloidogenic properties of a D/N mutated 12 amino acid fragment of the C-terminal domain of the Cholesteryl-Ester Transfer Protein (CETP)
The functionally critical C-terminal domain of CETP was studied using peptides derived from this region carrying the D470N mutation, which had previously been shown to alter the domain's conformation outside a lipid environment. Spectroscopic and fluorescence analysis showed the mutation favours a secondary beta-structure that promotes formation of peptide aggregates and fibrillar amyloid-like structures. These structures induced cytotoxicity in cultured microglial cells through generation of reactive oxygen species and disruption of endocytosis-controlling proteins, similar to effects seen with beta-amyloid fibrils. The authors propose that a fine balance between the C-terminal domain's dynamic secondary structure, its net charge, and the local microenvironment governs whether misfolding occurs, potentially altering the lipid-transfer function of CETP and favouring amyloidogenic behaviour.
Original abstract
The cholesteryl-ester transfer protein (CETP) facilitates the transfer of cholesterol esters and triglycerides between lipoproteins in plasma where the critical site for its function is situated in the C-terminal domain. Our group has previously shown that this domain presents conformational changes in a non-lipid environment when the mutation D(470)N is introduced. Using a series of peptides derived from this C-terminal domain, the present study shows that these changes favor the induction of a secondary β-structure as characterized by spectroscopic analysis and fluorescence techniques. From this type of secondary structure, the formation of peptide aggregates and fibrillar structures with amyloid characteristics induced cytotoxicity in microglial cells in culture. These supramolecular structures promote cell cytotoxicity through the formation of reactive oxygen species (ROS) and change the balance of a series of proteins that control the process of endocytosis, similar to that observed when β-amyloid fibrils are employed. Therefore, a fine balance between the highly dynamic secondary structure of the C-terminal domain of CETP, the net charge, and the physicochemical characteristics of the surrounding microenvironment define the type of secondary structure acquired. Changes in this balance might favor misfolding in this region, which would alter the lipid transfer capacity conducted by CETP, favoring its propensity to substitute its physiological function.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.